Deficits in sensory inhibition are a common symptom of schizophrenia and are correlated with certain positive symptoms. Improvement in symptomology is seen concurrent with improvement in sensory nhibition. The sensory inhibition deficit has been modeled in DBA/2 mice which not only show the deficient sensory inhibition, but are also genotypically similar to schizophrenics in having reduced numbers of alpha7 nicotinic receptors in the hippocampus and polymorphisms in the gene coding. We have recently shown that perinatal choline supplementation in the diet of the dam, produces DBA/2 offpspring with normal sensory nhibition. Perinatal choline supplementation in rats and one mouse strain (C57/BL6) has previously been shown to improve learning and memory in offspring thoughout their lifetimes. Our preliminary data show that sensory inhibition circuitry is also permanently altered in that there is a significant increase in apha7 nicotinic receptors in the dentate gyrus and CA1 regions of the hippocampus with peri-natal choline supplementation. The underlying mechanism of the improved sensory inhibition is not known. The present application will seek to elucidate the mechanism(s) by assessing role of alpha/ receptors (using alpha7 null mutant mice), the role of non-alpha7 receptors (using an agonist at both alpha7 and non-alpha7 receptors compared to an agonist at alpha7 receptors which is also an antagonist at alpha4beta2 receptors), and the role of DNA methylation (using an alternate methyl donor, and additionally, a genetically altered mouse strain with hypermethylation). Since learning and memory effects have been observed with peri-natal choline administration, all groups will be tested for learning and memory alterations. Finally, any changes in hippocampal alpha7 receptor levels induced by any of the perinatal interventions as well as the hypermethylation mice mice will be assessed using quantitative autoradiography. The data from these studies may potentially impact guide lines for human prenatal nutrition in at-risk pregnancies for schizophrenia. [unreadable] [unreadable] [unreadable]